Abstract Excess visceral fat (VF) has been strongly linked with development of insulin resistance and subsequent type 2 diabetes (T2DM) in humans, and rodent lipectomy studies have demonstrated that this relationship is causal. Among the nearly 30 million US adults affected by T2DM, disease onset typically appears secondary to weight gain, with excess VF considered to be a major driver. Lifestyle changes (diet and exercise) are the first line of treatment for weight management and disease prevention, but such efforts have not proven effective over the long-term. Surgically removing subcutaneous fat by large volume liposuction has been explored as an alternative approach, but the vast majority of these studies have failed to consistently demonstrate improvement in metabolic outcomes. Therefore, targeting the VF depots for removal should be prioritized in order to rapidly and significantly improve metabolic and overall health in humans. However, due to the heavy vascularization and other delicate structures within and around VF, there are currently no feasible methods to perform this procedure. Studies targeting the omentum have been conducted with mixed results, likely because this depot only accounts for a fraction of total VF mass (~10%) in an obese human. Thus, additionally targeting the mesentery and peri- renal areas, where most VF is harbored, may be required to surgically treat T2DM. To this end, we have developed and commercialized a technology in use for removal of cataracts as well as subcutaneous fat depots, which we refer to as Tissue Liquefaction Technology? (TLT). Our method is a unique, patented approach that delivers low levels of thermal and mechanical energy as a stream of warmed, low-pressurized, and pulsed saline, which causes susceptible non-connective tissues to undergo a phase transition from solid to liquid, while connective tissue-protected blood vessels and nerves are unharmed. Preliminary data demonstrate our ability to successfully target and remove these deep VF depots in pigs and baboons. Thus, the Specific Aim of this proposal is to determine feasibility and efficacy of large-volume VF removal in the baboon to reverse insulin resistance. This will be determined by surgically removing significant quantities of fat from all three VF depots (~75% of omentum, peri-renal, mesenteric fat) with TLT in 7 overweight and insulin resistant baboons, and determining effects on metabolic outcomes using `gold standard' techniques, including hyperinsulinemic- euglycemic clamps, DXA, MRI, MRS and a broad array of plasma metabolites at pre-determined intervals over 9 mo follow up. We have chosen to study insulin resistant baboons, since they are a well-validated model of human metabolism, and TLT has proven to easily and rapidly liquefy baboon (and human) VF in our preliminary studies. Our expectation is that animals will demonstrate exceptional recoveries, free of complications, have improved insulin sensitivity, without significant regrowth of VF depots or adverse effects on liver and skeletal muscle. In summary, our technology is a significant step forward for surgical fat removal, and if proven successful here, may represent a revolutionary treatment option for insulin resistance in T2DM and other conditions.